Air-stable racemization catalyst for dynamic kinetic resolution of secondary alcohols at room temperature

Article abstract of DOI:10.1021/ol051889x

(Chemical Equation Presented) A novel racemization catalyst was synthesized for the dynamic kinetic resolution (DKR) of alcohols with a lipase at room temperature in the air. Furthermore, a polymer-supported derivative was also synthesized and tested as a recyclable catalyst for the aerobic DKR of alcohols.

Full text of DOI:10.1021/ol051889x

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4523-4526
Air-Stable Racemization Catalyst for
Dynamic Kinetic Resolution of
Secondary Alcohols at Room
Temperature
Namdu Kim, Soo-Byung Ko, Min Serk Kwon, Mahn-Joo Kim,* and Jaiwook Park*
National Research Laboratory of Chirotechnology, Department of Chemistry,
DiVision of Molecular and Life Sciences, Pohang UniVersity of Science and
Technology (POSTECH), San 31 Hyojadong, Pohang 790-784, Korea
pjw@postech.ac.kr
Received August 5, 2005
ABSTRACT
A novel racemization catalyst was synthesized for the dynamic kinetic resolution (DKR) of alcohols with a lipase at room temperature in the
air. Furthermore, a polymer-supported derivative was also synthesized and tested as a recyclable catalyst for the aerobic DKR of alcohols.
Methods for preparing optically pure compounds are of great
importance in pharmaceutical, agrochemical, and other fine
chemical industries. One of the most popular methods is the
kinetic resolution (KR) of racemic mixtures by enzymes such
as lipases and esterases.1 However, the KR has an intrinsic
limitation; the yield of a desired enantiomer is less than 50%.
Dynamic kinetic resolution (DKR), in which in situ racem-
ization of unwanted enantiomers is coupled with KR, is an
attractive method to overcome the limitation.2 Several groups
have reported transition-metal racemization catalysts that are
compatible with the enzymatic systems for the DKR.3 Our
group has reported a ruthenium catalyst (1) that can be
combined with lipase or subtilisin to convert racemic
secondary alcohols into the corresponding optically pure
acetates in (R)- or (S)-forms at room temperature (Figure
1).4 Recently, a more active racemization catalyst (2) has
been reported by Ba¨ckvall et al.; the DKR of secondary
alcohols can be completed in 3 h at room temperature.5
However, all of the transition-metal racemization catalysts
reported so far require anaerobic conditions due to their air
(1) (a) Waldmann, K. D. H. Enzyme Catalysis in Organic Synthesis: A
ComprehensiVe Handbook, 2nd ed.; Waldmann, K. D. H., Ed.; Wiley-
VCH: Weinheim, 2002; Vols. I-III. (b) Faber, K. In Biotransformations
in Organic Chemistry, 4th ed.; Springer: Berlin, 2000.
(2) (a) Faber, K. Chem. Eur. J. 2001, 7, 5005. (b) Caddick, S.; Jenkins,
K. Chem. Soc. ReV. 1996, 447. (c) Noyori, R.; Tokunaga, M.; Kitamura,
K. Bull. Chem. Soc. Jpn. 1995, 68, 36. (d) Ward, R. S. Tetrahedron:
Asymmetry 1995, 6, 1475.
(3) (a) Pa`mies, O.; Ba¨ckvall, J.-E. Trends Biotechnol. 2004, 22, 130.
(b) Pa`mies, O.; Ba¨ckvall, J.-E. Chem. ReV. 2003, 103, 3247. (c) Kim, M.-
J.; Ahn, Y.; Park, J. Bull. Kor. Chem. Soc. 2005, 26, 515. (d) Kim, M.-J.;
Ahn, Y.; Park, J. Curr. Opin. Chem. Biol. 2002, 13, 578. (e) Gihani, M. T.
E.; Williams, J. M. J. Curr. Opin. Chem. Biol. 1999, 3, 11. (f) Dijksman,
A.; Elzinga, J. M.; Li, Y.-X.; Arends, I. W. C. E.; Sheldon, R. A.
Tetrahedron: Asymmetry 2000, 13, 879. (g) Reetz, M. T.; Schimossek, K.
Chimia 1996, 50, 668.
10.1021/ol051889x CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/25/2005

Table 1. Racemization of (S)-1-Phenylethanola
entry
catalyst
base
atmosphere
% eeb,c
1
2
3
4
5
6
7
3a
3a
3a
3a
3a
3b
3c
t-BuOK
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
argon
argon
argon
air
O2 (1 atm)
air
45 (59)
25 (64)
0 (65)
0 (73)
3 (67)
13 (77)
10 (51)
air
a (S)-1-Phenylethanol (>99% ee, 0.25 mmol) dissolved in toluene (0.80
mL) was added to a flask containing 3 (4.0 mol %) and base (1.0 equiv)
and stirred at 25 °C for 2.5 h. b Measured by HPLC equipped with a chiral
column (Chiralcel OD, Daicel). c Numbers in parentheses show the % ee
of 1-phenylethanol after 30 min.
Figure 1. Racemization catalysts.
the racemization of (S)-1-phenylethanol was completed in
2.5 h with 4 mol % of 3a at room temperature in the air
(entry 4). The racemization was possible even under an
oxygen atmosphere (entry 5). The chloride derivative (3a)
was better than the bromide (3b) or the iodide (3c) (entries
4, 6, and 7) in the air.
sensitivity during DKR and, therefore, are not reusable.6
Herein, we report an air-stable and recyclable racemization
catalyst (3) that is applicable to alcohol DKR at room
temperature. We also report a heterogeneous version (4) of
3 for more efficient recovery and reuse.
The DKR of racemic 1-phenylethanol was carried out with
the ruthenium complexes 3a-c to find the optimum condi-
tions (Table 2). Toluene was a better solvent than polar ones
On the basis of the known synthetic method for a
methoxycyclopentadienyl ruthenium complex (3c),7 benzyl-
oxy derivatives (3a and 3b) were prepared by the reaction
of [Ph4(η4-C4CO)]Ru(CO)3 (5) with benzyl chloride and with
benzyl bromide,8 respectively (Scheme 1).
Table 2. Dynamic Kinetic Resolution of 1-Phenylethanola
catalyst
(mol %)
yieldb
(%)
Scheme 1. Synthesis of O-Alkyl(tetraphenyl)cyclopentadienyl
Ruthenium Complexes 3
entry
atmosphere
solvent
% eec
1
2
3
4
5
6
7
3a (4.0)
3a (4.0)
3a (4.0)
3a (1.0)
3a (4.0)
3b (4.0)
3c (4.0)
argon
argon
argon
argon
air
acetone
EtOAc
55
57
>99
85
>99
67
57
>99
>99
>99
>99
>99
>99
>99
toluene
toluene
toluene
toluene
toluene
air
air
a 1-Phenylethanol (1.0 mmol) dissolved in a solvent (3 mL) was added
to a flask containing 3, K3PO4 (1.0 mmol), Novozym 435 (8 mg), and
isopropenyl acetate (1.5 mmol) at 25 °C. b Measured by GC after 20 h.
c Measured by GC equipped with a chiral column (BETA DEX 120,
Supelco).
The ruthenium complexes were tested for the racemization
of (S)-1-phenylethanol under various conditions (Table 1).
The choice of a proper base was crucial; potassium phosphate
displayed satisfactory performance, while potassium tert-
butoxide decomposed the ruthenium complexes. Notably,
contrary to known transition-metal-catalyzed racemizations,
such as acetone and ethyl acetate (EtOAc). As in the
racemization, 3a was the best catalyst and active in the air.
The synthetic method for 3 was applied to the preparation
of a polymer-bound derivative (4) (Scheme 2). Hydroxyl-
methyl polystyrene (6) was reacted with 4-(chloromethyl)-
benzoyl chloride to attach chlorobenzyl groups.9 Heating a
mixture of the resulting polymer 7 and [Ph4(η4-C4CO)]Ru-
(CO)3 (5) gave the polymer-supported catalyst 4.10 Then, the
reusability of 4 was tested in the DKR of 1-phenylethanol
under conditions similar to those for entry 5 of Table 2: first
run, >99%, >99% ee; second run, >99%, >99% ee; third
(4) (a) Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.; Kim, E. J.;
Kim, M.-J.; Park, J. J. Org. Chem. 2004, 69, 1972. (b) Kim, M.-J.; Chung,
Y. I.; Choi, Y. K.; Lee, H. K.; Kim, D.; Park, J. J. Am. Chem. Soc. 2003,
125, 11494. (c) Choi, J. H.; Kim, Y. H.; Nam, S. H.; Shin, S. T.; Kim,
M.-J.; Park, J. Angew. Chem., Int. Ed. 2002, 41, 2373.
(5) (a) Mart´ın-Matute, B.; Edin, M.; Boga´r, K.; Kaynak, F. B.; Ba¨ckvall,
J.-E. J. Am. Chem. Soc. 2005, 127, 8817. (b) Mart´ın-Matute, B.; Edin, M.;
Boga´r, K.; Ba¨ckvall, J.-E. Angew. Chem., Int. Ed. 2004, 43, 6535.
(6) The complexes 1 and 2 were active in the air for the racemization of
(S)-1-phenylethanol in the presence of K3PO4. However, the DKR of (S)-
1-phenylethanol with them gave (R)-1-phenylethyl acetate in 67% and 58%
yield, respectively, after 20 h under the aerobic conditions.
(7) Schneider, B.; Goldberg, I.; Reshef, D.; Stein, Z.; Shvo, Y. J.
Organomet. Chem. 1999, 588, 92.
(9) Hydroxymethyl polystyrene (100-200 mesh, 1% divinylbenzene;
substitution: 1.13 mmol/g) was purchased from Novabiochem.
(10) The resulting polymer (3.37 wt % Ru) was characterized by IR.
See the Supporting Information.
(8) See the Supporting Information.
4524
Org. Lett., Vol. 7, No. 20, 2005

Table 3. DKR of Secondary Alcoholsa
Scheme 2. Synthesis of a Polymer-Bound Racemization
Catalyst
run, 95%, >99% ee; fourth run, 36%, >99% ee.11 In the
fourth run, the reaction mixture became a thick suspension.
Meanwhile, the optical purity of the unreacted 1-phenyl-
ethanol was 39% ee. These observations indicate that
inefficient stirring and/or decreased enzyme activity is the
major cause of the drastic yield drop.
On the basis of the results from the DKR of 1-phenyle-
thanol, the scope of our catalysts 3a and 4 was investigated
in the DKR of various secondary alcohols (Table 3). Our
catalyst systems displayed high efficiency toward benzylic
alcohols (entries 1-12) as well as aliphatic ones (entries
13-21). The catalytic activity of 4 was practically same as
that of 3a. Electronic effect on the reaction rate for the
benzylic alcohols was not significant. 1-Phenylethanol, 1-(4-
methylphenyl)ethanol, and 1-(4-chlorophenyl)ethanol were
resolved completely in 20 h, while 1-(4-methoxyphenyl)-
ethanol required a little longer reaction time (30 h) (entry
7). Naphthyl derivatives also gave excellent results in yield
and enantioselectivity (entries 8-11). The DKR of 1-indanol
was less enantioselective than those of other benzylic
alcohols (entry 12). An excellent result in enantioselectivity
and yield was obtained for 1-cyclohexylethanol, although a
longer reaction time (72 h) is needed (entry 13). However,
heating at 50 °C increased the reaction rate satisfactorily
(entries 14-15). For linear aliphatic alcohols such as
2-octanol and 4-phenyl-2-butanol, reducing the amount of
the lipase to suppress the acylation of (S)-isomer as well as
heating (50 °C) were needed for satisfactory results in both
yield and enantioselectivity (entries 16-21).
NMR experiments were carried out to get clues to explain
the racemization. Interestingly, except for the resonances for
3a and 1-phenylethanol, there were no resonances that show
the formation of new species such as a ruthenium hydride,
a A mixture of alcohol (1.0 mmol), 3a (4 mol %), K3PO4 (1.0 mmol),
Novozym 435 (8 mg), and isopropenyl acetate (1.5 mmol) in toluene (3
mL) was stirred at 25 °C for 20 h. b Determined by GC. c Numbers in
parentheses show isolated yields. d Determined by GC equipped with a chiral
column (BETA DEX 120, Supelco). e After 30 h. f Determined by HPLC
equipped with a chiral column (chiralcel OD, Daicel). g After 72 h. h After
20 h at 50 °C. i The amount of Novozym 435 was reduced to 4 mg.
1
a ruthenium alkoxide, and acetophenone in the H and 13C
NMR spectra of a toluene-d8 solution containing 3a, potas-
(11) When the DKR was completed, the reaction mixture was extracted
with hexane five times. The residue was dried under vacuum and stored
for reuse.
Org. Lett., Vol. 7, No. 20, 2005
4525

sium phosphate, and 1-phenylethanol.8 An explanation would
be that an equilibrium between the ruthenium chloride 3a
and active species is far shifted toward 3a.
Acknowledgment. We are grateful for the financial
supports from the Korean Ministry of Science and Technol-
ogy through KISTEP (NRL program) and KOSEF (the
Center for Integrated Molecular System) and the Korean
Ministry of Education through KRF (the BK21 program).
In summary, we have demonstrated for the first time that
a chemoenzymatic alcohol DKR in the air is possible by the
combination of a readily preparable ruthenium catalyst and
an immobilized lipase. Furthermore, a heterogeneous deriva-
tive has been synthesized by coupling a ruthenium tricarbonyl
complex (5) and a polymer containing (chloromethyl)benzoyl
moieties. Our synthetic method for the ruthenium catalysts
can be modified to develop more practical catalyst systems
for alcohol DKR.
Supporting Information Available: Synthetic procedures
for 3a,b, 4, and 7 and the NMR spectra of a mixture of 3a,
K3PO4, and 1-phenylethanol). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL051889X
4526
Org. Lett., Vol. 7, No. 20, 2005